A physiological and translational liver model to study the metabolism-modulating roles of extracellular matrix microstructures

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ABSTRACT My laboratory has been dedicated to developing physiologically relevant yet easy-to-apply tissue modeling technologies, and exploring the interactions between extracellular matrix (ECM) microstructures and cell metabolisms. Building on recent successes and discoveries, we propose to develop a more advanced technology for liver modeling, and to profoundly study how fibrosis-relevant ECM microstructures can impair hepatic metabolism—the former aims to reduce the monetary/time costs and human subject risks in new drug development, and the latter will provide new understanding and metabolic targets for fibrosis treatments. Although various microfluidic liver models have been reported, they lack the critical compositions of the physiological liver, namely, all the necessary cell types, the relevant architecture, and physiological 3D ECMs. Both literature and our preliminary results suggest the crucial roles of these components in maintaining hepatic functions and homeostasis, which may explain why current liver models could only mimic part of the functions. Integrating the various cell types, the cellular architecture, and the 3D ECMs represents challenging hurdles by the available technologies. Therefore, we propose an innovative technology to model the liver with a new fabrication logic, workflow, and set of technical means. This technology will recapitulate the most liver niche properties heretofore, but with relatively simple and straightforward operations (setting up, maintenance, analyses, etc.). We recently reported for the first time that ECM microstructures could modulate metabolic activities in various cell types. Based on this, we propose to set up ECM controls that mimic healthy and fibrotic conditions, and thoroughly investigate how the aberrantly remodeled ECMs can impair hepatic metabolisms. Mechanistic studies involving integrins and AMP-activated protein kinase are also planned. To summarize, there has not been a tissue modeling technology like the proposed one; and others have not reported the interactions between ECM microstructures and cell metabolism. The proposed work, therefore, represents high novelty and my laboratory’s unique space in the field. Completing the proposed studies will be significant for pharmaceutical developments because a new testing/screening platform and metabolic (metabolites and the controlling proteins) targets will be provided for future fibrosis therapies.